Kryshchyshyn-Dylevych A. 4-Thiazolidinones and related heterocycles in the design of antiparasitic and antitumor agents as polypharmacological drug-like molecules.

Object - structure design, synthetic methods, chemical, physicochemical and biological properties, structure-activity relationship; prediction of polypharmacological properties; mechanisms of biological effects realization of 5-ene-4-thiazolidinones, thiopyranothiazoles and related heterocyclic systems; aim - directed design and synthesis of new derivatives of 5-ene-4-thiazolidinones, thiazolidinone/thiazole-indole/imidazothiadiazole hybrid molecules, thiazole-containing polycyclic compounds and their bioisostere conjugates as potential "drug-like molecules" with polypharmacological profile including anticancer, antiparasitic and antimicrobial activity; methods - classical organic synthesis, synthesis using microwave irradiation; physico-chemical methods of the structure analysis, in silico and statistical methods, in vitro and in vivo pharmacological studies; novelty – an applied value of the polypharmacological approach in the development of drug-like molecules as antiproliferative agents with dual antiparasitic and/or antitumor activities is substantiated. Based on the methods of statistical evaluation of the dependence of the antitrypanosomal and antitumor activity parameters established for double-acting compounds, a mathematical model was developed to predict the antitumor effect of thiazolidinones on different cancer lines based on their antitrypanosomal activity. Methods for the synthesis and structural functionalization of 2-thioxo-4-thiazolidinone-3-carboxylic acid derivatives, which exhibit significant antitrypanosomal, antileishmanial and antitumor activity had been developed. The thiazole/thiazolidone-phenylindole/imidazothiadiazole hybrids with high trypanocidal and antileishmanial activity were synthesized within the hybrid-pharmacophore approach. New N-substituted derivatives of isothiochromenothiazoles and 9-aryl(heteryl)-azatetracyclotetradecenones-6 were synthesized, their antitrypanosomal activity was studied. Series of rhodanine-indolecarboxylic acids and their derivatives were synthesized and 5-fluoro-3- (4-oxo-2-thioxothiazolidin-5-ylidenemethyl)-1H-indole-2-carboxylic acid methyl ester with micromolar mean of GI50 values against whole cancer lines panel was identified. A number of new 5-arylidene-2-(4-hydroxyphenyl)-aminothiazol-4(5H)-ones had been synthesized, for which selective antileukemic activity was established. Results - double antiparasitic and antitumor activity of thiazolidinone-pyrazoline hybrid molecules has been proved. For a number of thiopyranothiazoles, antitrypanosomal and antileishmanial activity was established for the first time. Inhibition of tubulin polymerization has been established as one of the mechanisms of antitumor activity of 5-arylidene-2-aminothiazol-4(5H)-ons. Based on the in-depth biological studies, it was substantiated that 5-fluoro-3-(4-oxo-2-thioxothiazolidin-5-ylidenemethyl)-1H-indole-2-carboxylic acid methyl ester induces apoptosis via caspase 3-, PARP1- and Bax- protein-dependent pathways and causes DNA damage in HepG2 hepatocellular carcinoma cells. Derivatives of 5-aminomethylidene-rhodanine-3-propanoic acid, 2-(5-ylidene-4-oxo-2-thioxothiazolidin-3-yl)-succinimides and 5-aminomethylidene-2-ylidene-3-phenyl-4-thiazolidinone had been identified as highly active antifungal (Candida albicans) and antimicrobial (Staphylococcus aureus) agents; introduced - into the scientific process of higher education institutions; branch - pharmacy.